2. Academic Validation
  3. S100A4 Induces Neutrophilic Inflammation in Chronic Rhinosinusitis with Nasal Polyps via TLR4 Pathway

S100A4 Induces Neutrophilic Inflammation in Chronic Rhinosinusitis with Nasal Polyps via TLR4 Pathway

  • J Clin Immunol. 2025 Nov 15;45(1):160. doi: 10.1007/s10875-025-01953-4.
Yanyi Tu # 1 2 3 4,  Chunhao Li # 1 5,  Tao Li 1 2 3 4,  Jing Liu 6,  Linghui Meng 1 2 3 4,  Shengyang Liu 1 2 3 4,  Ping Li 1 2 3 4,  Yuzhu Wan 1 2 3 4,  Aiping Chen 1 2 3 4,  Li Shi 7 8 9 10,  De-Yun Wang 11
Affiliations

Affiliations

  • 1 Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, No. 4 Duanxing West Road, Jinan, 250000, Shandong, China.
  • 2 Department of Allergy, Shandong Provincial ENT Hospital, Shandong University, Jinan, China.
  • 3 Shandong Provincial Key Medical and Health Discipline of Allergy, Shandong Second Provincial General Hospital, Jinan, China.
  • 4 Shandong Provincial Key Medical and Health Laboratory of Airway Inflammatory Disease, Shandong Second Provincial General Hospital, Jinan, China.
  • 5 Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Peking, China.
  • 6 Department of Otolaryngology, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Rd, Singapore, 119228, Singapore.
  • 7 Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, No. 4 Duanxing West Road, Jinan, 250000, Shandong, China. [email protected].
  • 8 Department of Allergy, Shandong Provincial ENT Hospital, Shandong University, Jinan, China. [email protected].
  • 9 Shandong Provincial Key Medical and Health Discipline of Allergy, Shandong Second Provincial General Hospital, Jinan, China. [email protected].
  • 10 Shandong Provincial Key Medical and Health Laboratory of Airway Inflammatory Disease, Shandong Second Provincial General Hospital, Jinan, China. [email protected].
  • 11 Department of Otolaryngology, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Rd, Singapore, 119228, Singapore. [email protected].
  • # Contributed equally.
PMID: 41240201 DOI: 10.1007/s10875-025-01953-4
Abstract

Background: Treating neutrophilic inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP) remains a challenge. Managing excessive infiltration and activation of neutrophils in tissues is important for improving CRSwNP outcomes. S100A4, a calcium-binding protein, regulates cell migration, chemotaxis and tissue fibrosis. In this study, we sought to examine the role of S100A4 in neutrophilic inflammation in CRSwNP and its involvement in TLR4 signaling.

Methods: Quantitative RT-PCR and immunofluorescence were used to analyze the expression and cellular distribution of S100A4 in sinonasal mucosa. Primary human nasal epithelial cells (hNECs) were cultured and treated with S100A4 to assess cytokine and chemokine production. Additionally, we employed TLR4 Inhibitor (TAK-242) to investigate whether S100A4 exert this effect via TLR4 pathway.

Results: We found increased levels of S100A4 mRNA and S100A4+ cell number in CRSwNP patients compared with control, with the highest levels in uncontrolled and mixed eosinophilic-neutrophilic CRSwNP. Compared to eosinophils, S100A4 exhibits a stronger correlation with neutrophils. S100A4 was primarily located in inflammatory cells in lamina propria, with neutrophils forming the majority of S100A4+ cells. S100A4 treatment led to upregulation of neutrophil chemokines and pro-inflammatory cytokine IL-36γ, in nasal epithelia cells. S100A4 induced effect through TLR4 pathway, and can be inhibited by clarithromycin and dexamethasone.

Conclusion: S100A4 is elevated in neutrophilic CRSwNP and exerts its pro-inflammatory effect on nasal epithelial cells via TLR4 signaling cascade.

Keywords

Eosinophil; Nasal polyps; Neutrophil; S100A4; TLR4.

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